Reverse electron transfer results in a loss of flavin from mitochondrial Complex I. Potential mechanism for brain ischemia reperfusion injury

Anna Stepanova, Anja Kahl, Csaba Konrad, Vadim Ten, Anatoly S. Starkov, Alexander Galkin

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)
314 Downloads (Pure)

Abstract

Ischemic stroke is one of the most prevalent sources of disability in the world. The major brain tissue damage takes place upon the reperfusion of ischemic tissue. Energy failure due to alterations in mitochondrial metabolism and elevated production of reactive oxygen species (ROS) is one of the main causes of brain ischemia-reperfusion (IR) damage. Ischemia resulted in the accumulation of succinate in tissues, which favors the process of reverse electron transfer (RET) when a fraction of electrons derived from succinate is directed to mitochondrial complex I for the reduction of matrix NAD+.
We demonstrate that in intact brain mitochondria oxidizing succinate, complex I became damaged and was not able to contribute to the physiological respiration. This process is associated with a decline in ROS release and a dissociation of the enzyme’s flavin. This previously undescribed phenomenon represents the major molecular mechanism of injury in stroke and induction of oxidative stress after reperfusion. We also demonstrate that the origin of ROS during RET is flavin of mitochondrial complex I. Our study highlights a novel target for neuroprotection against IR brain injury and provides a sensitive biochemical marker for this process.
Original languageEnglish
Pages (from-to)3649-3658
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume37
Issue number12
Early online date15 Sep 2017
DOIs
Publication statusEarly online date - 15 Sep 2017

Keywords

  • flavin
  • ischemia
  • mitochondria
  • stroke
  • succinate

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